tbuckley/cabot-search huggingface dataset:
Abstract 6329: Using low-resolution, low-cost histopathology images to predict esophageal squamous cell carcinoma via deep learning
Authors: Mansoor Alam, Ibrar Amin, Ayesha Sajjad, Hina Zamir, Saad Zaheer, Maria T. Khattak, Iqbal Muhammad, Faisal F. Khan
Journal: Cancer Research (2022)

Abstract Like many cancers, esophageal squamous cell carcinoma, has a substantially better survival rate if detected in early stages, making early detection a critical element in successful treatment. On the other hand, deep learning tools that employ high-resolution whole slide images and therefore substantially greater compute power and are not easily accessible in low-resource settings. In this study we train and test deep learning models using low-resolution and low-cost digital histopathology images acquired using a 5-megapixel Leica ICC50 camera mounted on a Leica DM500 binocular microscope, at two different magnification levels, Under IRB approvals, we acquired a total of 64 Hematoxylin and Eosin (H&amp;E) stained tissue slides of biopsies taken from patient presenting at Rehman Medical Institute from 2016 to 2020 that were anonymized. A total of 2370 images were captured at two different magnification levels, i.e. 10x and 40x, and were labelled with four classes by at least one expert pathologist (677 well differentiated, 1066 moderately differentiated, 152 poor differentiated and 475 normal) to develop the ESCC image dataset. Preprocessing was performed to clean the dataset, generate patches and resize the images. Deep learning models were trained on the ESCC image dataset for feature extractions. This was followed by machine learning classifier for the diagnosis of ESCC. Deep learning models that were used in this study are Resnet50, VGG16, VGG19, and Inception_Resnet_V2 with Logistic Regression (LR) used as classifier. An ensemble model which stacks up the Inception and Resnet. This model preformed with the highest accuracy at 96% with Precision, Recall, and f1 score values at 96%, 96%, and 96%, respectively. This study reports 1) a local ESCC image repository for research purposes, 2) an ensemble ML/DL model that predicts ESCC with 96% accuracy and 3) also a computer-aided diagnosis (CAD) system for ESCC with a user-interface which will assist histopathologists in diagnosing ESCC with higher speed, efficiency and accuracy. Citation Format: Mansoor Alam, Ibrar Amin, Ayesha Sajjad, Hina Zamir, Saad Zaheer, Maria T. Khattak, Iqbal Muhammad, Faisal F. Khan. Using low-resolution, low-cost histopathology images to predict esophageal squamous cell carcinoma via deep learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6329.
Is It Ethical to Mandate Vaccination among Incarcerated Persons? Consider Enforcement and Ask People Living in Prisons and Jails
Authors: Jennifer E. James
Journal: The American Journal of Bioethics (2022)

"Is It Ethical to Mandate Vaccination among Incarcerated Persons? Consider Enforcement and Ask People Living in Prisons and Jails." The American Journal of Bioethics, ahead-of-print(ahead-of-print), pp. 1–2
A Fe(III)-porphyrin-oxaliplatin(IV) nanoplatform for enhanced ferroptosis and combined therapy
Authors: Xiaochun Hu, Ruihao Li, Wenjing Wu, Kang Fang, Zhounan Zhu, Yixuan Wang, Lulu Zhou, Mengyao Chen, Chunyan Dong, Shuo Shi
Journal: Journal of Controlled Release (2022)
Monoclonal antibody treatment drives rapid culture conversion in SARS-CoV-2 infection
Authors: Julie Boucau, Kara W. Chew, Manish C. Choudhary, Rinki Deo, James Regan, James P. Flynn, Charles R. Crain, Michael D. Hughes, Justin Ritz, Carlee Moser, Joan A. Dragavon, Arzhang C. Javan, Ajay Nirula, Paul Klekotka, Alexander L. Greninger, Robert W. Coombs, William A. Fischer, Eric S. Daar, David A. Wohl, Joseph J. Eron, Judith S. Currier, Davey M. Smith, Jonathan Z. Li, Amy K. Barczak
Journal: Cell Reports Medicine (2022)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies (mAbs) are among the treatments recommended for high-risk ambulatory persons with coronavirus 2019 (COVID-19). Here, we study viral culture dynamics post-treatment in a subset of participants receiving the mAb bamlanivimab in the ACTIV-2 trial (ClinicalTrials.gov: NCT04518410). Viral load by qPCR and viral culture are performed from anterior nasal swabs collected on study days 0 (day of treatment), 1, 2, 3, and 7. Treatment with mAbs results in rapid clearance of culturable virus. One day after treatment, 0 of 28 (0%) participants receiving mAbs and 16 of 39 (41%) receiving placebo still have culturable virus (p < 0.0001). Recrudescence of culturable virus is detected in three participants with emerging mAb resistance and viral RNA rebound. While further studies are necessary to fully define the relationship between shed culturable virus and transmission, these results raise the possibility that mAbs may offer immediate (household) and public-health benefits by reducing onward transmission.
A YAP/TAZ-TEAD signalling module links endothelial nutrient acquisition to angiogenic growth
Authors: Yu Ting Ong, Jorge Andrade, Max Armbruster, Chenyue Shi, Marco Castro, Ana S. H. Costa, Toshiya Sugino, Guy Eelen, Barbara Zimmermann, Kerstin Wilhelm, Joseph Lim, Shuichi Watanabe, Stefan Guenther, Andre Schneider, Francesca Zanconato, Manuel Kaulich, Duojia Pan, Thomas Braun, Holger Gerhardt, Alejo Efeyan, Peter Carmeliet, Stefano Piccolo, Ana Rita Grosso, Michael Potente
Journal: Nature Metabolism (2022)

Abstract Angiogenesis, the process by which endothelial cells (ECs) form new blood vessels from existing ones, is intimately linked to the tissue’s metabolic milieu and often occurs at nutrient-deficient sites. However, ECs rely on sufficient metabolic resources to support growth and proliferation. How endothelial nutrient acquisition and usage are regulated is unknown. Here we show that these processes are instructed by Yes-associated protein 1 (YAP)/WW domain-containing transcription regulator 1 (WWTR1/TAZ)-transcriptional enhanced associate domain (TEAD): a transcriptional module whose function is highly responsive to changes in the tissue environment. ECs lacking YAP/TAZ or their transcriptional partners, TEAD1, 2 and 4 fail to divide, resulting in stunted vascular growth in mice. Conversely, activation of TAZ, the more abundant paralogue in ECs, boosts proliferation, leading to vascular hyperplasia. We find that YAP/TAZ promote angiogenesis by fuelling nutrient-dependent mTORC1 signalling. By orchestrating the transcription of a repertoire of cell-surface transporters, including the large neutral amino acid transporter SLC7A5, YAP/TAZ-TEAD stimulate the import of amino acids and other essential nutrients, thereby enabling mTORC1 activation. Dissociating mTORC1 from these nutrient inputs—elicited by the loss of Rag GTPases—inhibits mTORC1 activity and prevents YAP/TAZ-dependent vascular growth. Together, these findings define a pivotal role for YAP/TAZ-TEAD in controlling endothelial mTORC1 and illustrate the essentiality of coordinated nutrient fluxes in the vasculature.
Transcatheter aortic valve implantation in patients with bicuspid valve morphology: a roadmap towards standardization
Authors: Tian-Yuan Xiong, Walid Ben Ali, Yuan Feng, Kentaro Hayashida, Hasan Jilaihawi, Azeem Latib, Michael Kang-Yin Lee, Martin B. Leon, Raj R. Makkar, Thomas Modine, Christoph Naber, Yong Peng, Nicolo Piazza, Michael J. Reardon, Simon Redwood, Ashok Seth, Lars Sondergaard, Edgar Tay, Didier Tchetche, Wei-Hsian Yin, Mao Chen, Bernard Prendergast, Darren Mylotte
Journal: Nature Reviews Cardiology (2022)
Abstract 6328: GPR56 as a therapeutic target for the development of antibody-drug conjugates for the treatment of colorectal cancer
Authors: Liezl E. Francisco, Treena Chatterjee, Zhengdong Liang, Sheng Zhang, Kendra Carmon
Journal: Cancer Research (2022)

Abstract Cancer stem cell (CSC) marker LGR5 is highly expressed in colorectal cancer (CRC) and has been considered as a therapeutic target for the treatment of CRC. Previously, we and others showed that CRC tumors were eliminated by treatment with LGR5-targeted antibody-drug conjugates (ADCs). However, a fraction of tumors eventually recurred, likely due to CSC plasticity or the ability of LGR5-positive CSCs to interconvert into more drug resistant LGR5-negative cancer cells. Through our efforts to identify underlying mechanisms of drug resistance and plasticity and develop therapies to eliminate CRC, we showed that GPR56 expression is increased with loss of LGR5 protein expression. GPR56 is a member of the adhesion G-protein coupled receptor (GPCR) family which mediates diverse functions, including cell adhesion and tumorigenesis. GPR56 is also upregulated in CRC and increased expression levels correlate with poor patient survival. We recently showed GPR56 can promote tumor growth and drug resistance of CRC cells through upregulation of multidrug resistance proteins. These findings identify GPR56 as a potential therapeutic target for the treatment of CRC. Presently, we are focused on the development and characterization of anti-GPR56 ADCs that selectively bind GPR56-high CRC cells to deliver potent cytotoxic drugs and destroy them. We reported the generation of unique anti-GPR56 monoclonal antibodies (mAbs) and are currently developing and optimizing GPR56-targeted ADCs conjugated with different drugs. Cell-based binding assays show that our anti-GPR56 mAb binds with high affinity and specificity to 293T cells overexpressing recombinant GPR56 or GPR56-high CRC cells, with no detectable binding to GPR56-negative cells. Using cytotoxicity assays, we evaluated the in vitro efficacy of anti-GPR56 ADCs against several CRC lines with different levels of GPR56 expression and showed that the ADC is only effective against CRC cells expressing GPR56. Moreover, we evaluated the therapeutic efficacy of our anti-GPR56-ADC against CRC cell line and patient-derived tumor xenograft models in vivo and demonstrated significant inhibition of tumor growth. Altogether, these findings suggest that novel GPR56-targeted ADCs may be a promising therapeutic strategy to overcome resistance for the improved treatment of CRC. Citation Format: Liezl E. Francisco, Treena Chatterjee, Zhengdong Liang, Sheng Zhang, Kendra Carmon. GPR56 as a therapeutic target for the development of antibody-drug conjugates for the treatment of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6328.
Single-cell analyses define a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer
Authors: Winston R. Becker, Stephanie A. Nevins, Derek C. Chen, Roxanne Chiu, Aaron M. Horning, Tuhin K. Guha, Rozelle Laquindanum, Meredith Mills, Hassan Chaib, Uri Ladabaum, Teri Longacre, Jeanne Shen, Edward D. Esplin, Anshul Kundaje, James M. Ford, Christina Curtis, Michael P. Snyder, William J. Greenleaf
Journal: Nature Genetics (2022)

To chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated single-cell chromatin accessibility profiles and single-cell transcriptomes from 1,000 to 10,000 cells per sample for 48 polyps, 27 normal tissues and 6 CRCs collected from patients with or without germline APC mutations. A large fraction of polyp and CRC cells exhibit a stem-like phenotype, and we define a continuum of epigenetic and transcriptional changes occurring in these stem-like cells as they progress from homeostasis to CRC. Advanced polyps contain increasing numbers of stem-like cells, regulatory T cells and a subtype of pre-cancer-associated fibroblasts. In the cancerous state, we observe T cell exhaustion, RUNX1-regulated cancer-associated fibroblasts and increasing accessibility associated with HNF4A motifs in epithelia. DNA methylation changes in sporadic CRC are strongly anti-correlated with accessibility changes along this continuum, further identifying regulatory markers for molecular staging of polyps.
Low-dose methylprednisolone treatment in critically ill patients with severe community-acquired pneumonia
Authors: G. Umberto Meduri, Mei-Chiung Shih, Lisa Bridges, Thomas J. Martin, Ali El-Solh, Nitin Seam, Anne Davis-Karim, Reba Umberger, Antonio Anzueto, Peruvemba Sriram, Charlie Lan, Marcos I. Restrepo, Juan J. Guardiola, Teresa Buck, David P. Johnson, Anthony Suffredini, W. Andrew Bell, Julia Lin, Lan Zhao, Lauren Uyeda, Lori Nielsen, Grant D. Huang, Khalid Bashir, Octavian Ioachimescu, Theresa Buck, David Johnson, Ali El Solh, Michael Frye, Ralph Panos, Mohammad Shatat, Enoch Gray, Brian Smith, Myron Kung, James Cutrell, Roger Bedimo, Peruvemba Sriram, Charlie Lan, Padmashi Rastogi, John Callaghan, Chadi Hage, Mark Plautz, Takako Schaninger, Richard Greenberg, Lennard Specht, Catherine Sassoon, Juan Guardiola, Julio Ramirez, Muthiah P Muthiah, Roland Schein, Andreea Antonesu-Turcu, Kathryn Rice, Houssein Youness, Lee Morrow, Ware Kuschner, Lilibeth Pineda, Richard Allen Robbins, Sharon Camhi, Matthew Jankowich, Waseem Ahmed, Thomas Martin, Mitchell Horowitz, John Nord, Mark Elstad, Marcos I Restrepo, Antonio Anzueto, Timothy Bigby, William Rodriguez-Cintron, Vincent Fan, Pratibha Kaul, Michael Habib, Nitin Seam, Guy Soo Hoo
Journal: Intensive Care Medicine (2022)
Antibodies to combat viral infections: development strategies and progress
Authors: Giuseppe Pantaleo, Bruno Correia, Craig Fenwick, Victor S. Joo, Laurent Perez
Journal: Nature Reviews Drug Discovery (2022)

Monoclonal antibodies (mAbs) are appealing as potential therapeutics and prophylactics for viral infections owing to characteristics such as their high specificity and their ability to enhance immune responses. Furthermore, antibody engineering can be used to strengthen effector function and prolong mAb half-life, and advances in structural biology have enabled the selection and optimization of potent neutralizing mAbs through identification of vulnerable regions in viral proteins, which can also be relevant for vaccine design. The COVID-19 pandemic has stimulated extensive efforts to develop neutralizing mAbs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with several mAbs now having received authorization for emergency use, providing not just an important component of strategies to combat COVID-19 but also a boost to efforts to harness mAbs in therapeutic and preventive settings for other infectious diseases. Here, we describe advances in antibody discovery and engineering that have led to the development of mAbs for use against infections caused by viruses including SARS-CoV-2, respiratory syncytial virus (RSV), Ebola virus (EBOV), human cytomegalovirus (HCMV) and influenza. We also discuss the rationale for moving from empirical to structure-guided strategies in vaccine development, based on identifying optimal candidate antigens and vulnerable regions within them that can be targeted by antibodies to result in a strong protective immune response.
The first-in-human phase I study of a brain-penetrant mutant IDH1 inhibitor DS-1001 in patients with recurrent or progressive IDH1-mutant gliomas
Authors: Atsushi Natsume, Yoshiki Arakawa, Yoshitaka Narita, Kazuhiko Sugiyama, Nobuhiro Hata, Yoshihiro Muragaki, Naoki Shinojima, Toshihiro Kumabe, Ryuta Saito, Kazuya Motomura, Yohei Mineharu, Yasuji Miyakita, Fumiyuki Yamasaki, Yuko Matsushita, Koichi Ichimura, Kazumi Ito, Masaya Tachibana, Yasuyuki Kakurai, Naoko Okamoto, Takashi Asahi, Soichiro Nishijima, Tomoyuki Yamaguchi, Hiroshi Tsubouchi, Hideo Nakamura, Ryo Nishikawa
Journal: Neuro-Oncology (2022)

Abstract Background Approximately 70% of lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in the accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG); this leads to epigenetic dysregulation, oncogenesis, and subsequent clonal expansion. DS-1001 is an oral brain-penetrant mutant IDH1 selective inhibitor. This first-in-human study investigated the safety, pharmacokinetics, pharmacodynamics, and efficacy of DS-1001. Methods This was a multicenter, open-label, dose-escalation, phase I study of DS-1001 for recurrent/progressive IDH1-mutant (R132) glioma (N = 47) (NCT03030066). DS-1001 was administered orally at 125-1400 mg twice daily. Dose-escalation used a modified continual reassessment method. Results The maximum tolerated dose was not reached. Eight patients were continuing treatment at the data cutoff. Most adverse events (AEs) were grade 1-2. Twenty patients (42.6%) experienced at least 1 grade 3 AE. No grade 4 or 5 AEs or serious drug-related AEs were reported. Common AEs (&amp;gt;20%) were skin hyperpigmentation, diarrhea, pruritus, alopecia, arthralgia, nausea, headache, rash, and dry skin. The objective response rates were 17.1% for enhancing tumors and 33.3% for non-enhancing tumors. Median progression-free survival was 10.4 months (95% confidence interval [CI], 6.1 to 17.7 months) and not reached (95% CI, 24.1 to not reached) for the enhancing and non-enhancing glioma cohorts, respectively. Seven on-treatment brain tumor samples showed a significantly lower amount of D-2-HG compared with pre-study archived samples. Conclusions DS-1001 was well tolerated with a favorable brain distribution. Recurrent/progressive IDH1-mutant glioma patients responded to treatment. A study of DS-1001 in patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 glioma is ongoing (NCT04458272).
Management of suspected and confirmed<scp>COVID</scp>‐19 (<scp>SARS‐CoV</scp>‐2) vaccine hypersensitivity
Authors: Margitta Worm, Aikaterina Alexiou, Andrea Bauer, Regina Treudler, Gerda Wurpts, Heinrich Dickel, Timo Buhl, Sabine Müller, Andreas Jung, Randolf Brehler, Joachim Fluhr, Ludger Klimek, Norbert Mülleneisen, Wolfgang Pfützner, Ulrike Raap, Stefani Roeseler, Sandra Schuh, Hartmut Timmermann, Guido Heine, Bettina Wedi, Knut Brockow
Journal: Allergy (2022)

Systemic allergic reactions to vaccines are very rare. In this study we assessed the management and outcome of suspected SARS-CoV-2 vaccine hypersensitivity.Totally, 334 individuals underwent an allergy work up regarding SARS-CoV-2 vaccination (group A: 115 individuals suspected to be at increased risk for vaccine-related reactions before vaccination and group B: 219 patients with reactions after COVID vaccination). The large majority of the SPT/IDT with the vaccines were negative; however, we identified in 14.1% (n = 47) a possible sensitization to the SARS-CoV-2 vaccine and/or its ingredients defined as one positive skin test. Of the 219 individuals (group B) who experienced symptoms suspicious for a hypersensitivity reaction after vaccination, 214 were reported after the first vaccination with a mRNA vaccine (157 mRNA (Comirnaty®, 38 Spikevax®) and 18 with a vector vaccine (Vaxzevria®), 5 cases were after the second vaccination.The symptom profile in group B was as follows: skin symptoms occurred in 115 cases (n = 59 angioedema, n = 50 generalized urticaria and n = 23 erythema/flush. Seventy individuals had cardiovascular, 53 respiratory and 17 gastrointestinal symptoms. Of the overall 334 individuals, 78 patients tolerated (re)-vaccination (out of skin test positive/negative 7/19 from group A and 17/35 from group B).Proven IgE-mediated hypersensitivity to SARS-CoV-2 vaccines is extremely rare and not increased in comparison with reported hypersensitivity to other vaccines. The value of skin tests is unclear and nonspecific reactions, in particular when intradermal testing is applied, should be considered.
Racism is wrecking the lives of doctors, affecting patient care, and jeopardising services
Authors: Chaand Nagpaul
Journal: BMJ (2022)

Racism is wrecking the lives of doctors, affecting patient care, and jeopardising services Chaand Nagpaul council chairIn an NHS built upon a founding principle to treat all patients equally regardless of who they are, it's a shameful reality that this principle does not apply to its workforce, with evidence established of racial inequality and discrimination running rife within the medical profession.
Impact of pre-existing background therapy on placebo responses in randomised controlled clinical trials of rheumatoid arthritis
Authors: Andreas Kerschbaumer, Zaïda Iasha Rivai, Josef S Smolen, Daniel Aletaha
Journal: Annals of the Rheumatic Diseases (2022)

Various hypotheses exist for the explanation of placebo response rates in randomised controlled trials (RCTs) of patients with rheumatoid arthritis with IR to methotrexate (MTX). We hypothesised that placebo responses may be related to more consequent intake of MTX during the tightly monitored trial period.We conducted a post hoc analysis of placebo-treated patients included in two RCTs that had allowed inclusion of patients with and without ongoing MTX: the GO-AFTER and the SIRROUND-T trials. We pooled placebo patients of both trials and compared American College of Rheumatology (ACR) 20%/50%/70% response rates and Clinical Disease Activity Index (CDAI) low disease activity (LDA; ie, CDAI ≤10) responses between those receiving placebo on top of continued MTX and those receiving placebo without any background disease modifying antirheumatic drugs (DMARDs).Of 398 placebo patients, 285 continued MTX and 113 had no background DMARDs. Baseline characteristics were similar. At week 16, ACR20 response was achieved by 72/285 (25.3%) of placebo+continued MTX and 14/113 (12.4%) of placebo only patients (nominal p=0.005); for ACR50 these numbers were 25/285 (8.4%) versus 1/113 (0.9%; nominal p=0.003) and for ACR70 they were 8/285 (2.8%) versus 0/113 (0%; nominal p=0.112). Also, more patients with placebo+continued MTX achieved CDAI-LDA at week 16 (25/285; 8.8%) compared with placebo only (2/113; 1.8%; nominal p=0.013).Clinical responses to placebo are higher in patients who continue an insufficient MTX background therapy. This suggests an inadvertently more consequent intake of background therapy during the trial. Background therapy should therefore be effectively aligned before enrollment into a clinical trial.
Limited disassembly of cytoplasmic hepatitis B virus nucleocapsids restricts viral infection in murine hepatic cells
Authors: Kaitao Zhao, Fangteng Guo, Jingjing Wang, Youquan Zhong, Junzhu Yi, Yan Teng, Zaichao Xu, Li Zhao, Aixin Li, Zichen Wang, Xinwen Chen, Xiaoming Cheng, Yuchen Xia
Journal: Hepatology (2022)

Murine hepatic cells cannot support hepatitis B virus (HBV) infection even with supplemental expression of viral receptor, human sodium taurocholate cotransporting polypeptide (hNTCP). However, the specific restricted step remains elusive. In this study, we aimed to dissect HBV infection process in murine hepatic cells.Cells expressing hNTCP were inoculated with HBV or hepatitis delta virus (HDV). HBV pregenomic RNA (pgRNA), covalently closed circular DNA (cccDNA), and different relaxed circular DNA (rcDNA) intermediates were produced in vitro . The repair process from rcDNA to cccDNA was assayed by in vitro repair experiments and in mouse with hydrodynamic injection. Southern blotting and in situ hybridization were used to detect HBV DNA. HBV, but not its satellite virus HDV, was restricted from productive infection in murine hepatic cells expressing hNTCP. Transfection of HBV pgRNA could establish HBV replication in human, but not in murine, hepatic cells. HBV replication-competent plasmid, cccDNA, and recombinant cccDNA could support HBV transcription in murine hepatic cells. Different rcDNA intermediates could be repaired to form cccDNA both in vitro and in vivo . In addition, rcDNA could be detected in the nucleus of murine hepatic cells, but cccDNA could not be formed. Interestingly, nuclease sensitivity assay showed that the protein-linked rcDNA isolated from cytoplasm was completely nuclease resistant in murine, but not in human, hepatic cells.Our results imply that the disassembly of cytoplasmic HBV nucleocapsids is restricted in murine hepatic cells. Overcoming this limitation may help to establish an HBV infection mouse model.